AU8863698A

AU8863698A - Process for the preparation of 2-alkylthiobenzonitrile derivatives

Info

Publication number: AU8863698A
Application number: AU88636/98A
Authority: AU
Inventors: Didier Bernard; Alain Truchon
Original assignee: Rhone Poulenc Agro SA; Rhone Poulenc Agrochimie SA
Current assignee: Bayer CropScience SA
Priority date: 1997-07-07
Filing date: 1998-07-03
Publication date: 1999-02-08
Anticipated expiration: 2018-07-03
Also published as: AU756271B2; PL337895A1; JP2001509502A; US6506926B1; BR9810687A; GB9714306D0; KR100573559B1; BR9810687B1; WO1999002490A1; IL133815A; IL133815A0; EP0994852B1; EP0994852A1; TW528744B; CN1143846C; JP4172612B2; DE69819504D1; ZA985771B; KR20010015546A; HUP0003321A2

Abstract

A process for preparing a compound of the formula:which comprises reacting a compound of the formula:wherein R3 is nitro or halo, with a compound of formula R1S-X wherein X is hydrogen or alkali metal.

Description

WO 99/02490 PCT/EP98/04948

-I

PROCESS FOR THE PREPARATION OF 2-ALKYLTHIOBENZONITRILE DERIVATIVES 5 This invention relates to a process for preparing certain 2-alkylthio substituted benzonitriles, which are useful as chemical intermediates, for example in the preparation of herbicidally active compounds. 2-Alkylthio-substituted benzonitriles are intermediates in the preparation of agrochemicals such as herbicides, for example as 10 described in EP 0527036. It is desirable to provide such compounds in high yields and also to develop new procedures which allow the efficient displacement of 2-nitro or 2-halo substituted benzonitriles to furnish 2 alkylthio substituted benzonitriles. The present invention seeks to provide a high yielding process for 15 preparing 2-alkylthio substituted benzonitriles. Thus, the present invention provides a process for preparing a 2-alkylthio-substituted-benzonitrile derivative of formula (I): CN SRI R4

R

2 (I) 20 wherein R 1 represents C1- 6 alkyl; WO 99/02490 PCTIEP98/04948 -2

R

2 represents C 1

-

6 haloalkyl, C1- 6 alkyl. C 1

-

6 haloalkoxy, C 1 -6 alkoxy, SOnR 5 or halogen;

R

4 represents hydrogen, C1- 6 haloalkoxy, C 1

-

6 alkoxy, SOnR 5 or halogen; or a 5 or 6-membered heterocyclic ring (which may be 5 unsaturated or partially saturated) containing 1 to 3 hetero atoms selected from oxygen, nitrogen and sulphur, optionally substituted by halogen, C1- 6 haloalkyl, C1- 6 alkyl, C1- 6 haloalkoxy, C1- 6 alkoxy, SOnR5, nitro or cyano;

R

5 represents C 1-6 alkyl; and 10 n represents 0, 1 or 2; which comprises reacting a compound of formula (II): CN R3 R4 R2 (II) wherein R 2 and R 4 are as hereinbefore defined and R 3 represents 15 nitro or a halogen atom selected from fluorine, chlorine and bromine, with a compound of formula R 1 S-X, wherein R 1 is as hereinbefore defined and X is hydrogen or an alkali metal.

WO 99/02490 PCT/EP98/04948 -3 When R 4 represents a heterocyclic ring, preferred rings include 3-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 5-oxazolyl, 2-fury), 3-furyl, 2 thienyl and 3-thienyl. RI preferably represents methyl. 5 R 2 preferably represents trifluoromethyl.

R

3 preferably represents nitro or chlorine.

R

4 preferably represents hydrogen. X preferably represents a sodium, potassium or lithium atom. In an especially preferred embodiment of the invention R 1 10 represents C 1-6 alkyl (methyl is most preferred);

R

2 represents C 1-6 haloalkyl (trifluoromethyl is most preferred);

R

3 represents nitro or a halogen atom selected from fluorine, chlorine and bromine (nitro or chlorine are most preferred); and

R

4 represents hydrogen. 15 The above reaction to prepare compounds of formula (I) by the reaction of a compound of formula (II) with a compound of formula

R

1 S-X may be performed using various solvents such as aromatic hydrocarbons for example toluene or xylene, ethers such as 20 tetrahydrofuran, dioxan or tert-butyl methyl ether; amides such as N,N dimethylformamide; sulphoxides such as dimethylsulphoxide; or ketones, for example methyl ethyl ketone or acetone. An especially WO 99/02490 PCT/EP98/04948 -4 preferred solvent is acetone, optionally in the presence of water. It has been found that the reaction proceeds in excellent yield using these conditions. A preferred compound of formula R 1 S-X is sodium 5 thiomethoxide, which may be used in dry solid form or conveniently as a solution in water. Where X is hydrogen, a base is generally present in the reaction mixture. Examples of suitable bases are alkali metal or alkaline earth metal carbonates, alkoxides or hydrides such as potassium carbonate, 10 potassium t-butoxide or sodium hydride, or amidine bases such as 1,8 diazabicyclo[5.4.0]undec-7-ene or 1,1,3,3-tetramethylguanidine. The reaction is generally performed at a temperature from about -20 0 C to about 120 0 C preferably from about 100 to about 60 0 C and most preferably from about 100 to about 40oC. 15 The molar ratio of the benzonitrile derivative of formula (II): alkyl thiol (or metal salt thereof) of formula R 1 S-X is generally from about 1:1 to about 1:4, preferably from about 1:1 to about 1:2.5 and most preferably from about 1:1 to about 1:1.2. Optionally the reaction may be performed in a two phase system 20 consisting of water and another solvent which has low solubility in water, in the presence a phase transfer catalyst. Examples of phase transfer catalysts which are suitable include ammonium salts such as tetrabutylammonium chloride; phosphonium salts such as WO 99/02490 PCT/EP98/04948 -5 tributylhexadecylphosphonium bromide; guanidinium salts such as hexaethylguanidinium chloride or hexamethylguanidinium chloride; or crown ethers such as 18-crown-6. Suitable solvents for use with water and the phase transfer catalyst include aromatic hydrocarbons for 5 example toluene or xylene, ethers such as tert-butyl methyl ether, halogenated solvents such as chlorobenzene or dichloromethane, generally employed in admixture with water. The quantity of phase transfer catalyst employed is generally from a 2 to 10% molar ratio (relative to the molar amount of compound of formula (II)). When 10 conducted under these conditions the reaction is generally carried out at a temperature of from about 5oC to about 100C, preferably from about 250 to about 70 0 C. The following non-limiting examples illustrate the invention. 15 Example 1 Preparation of 2 -methylthio-4-trifluoromethylbenzonitrile Sodium thiomethoxide (366g of a 21% aqueous solution, 1.1M) was added during 3 hours to a solution of 2-nitro-4 trifluoromethylbenzonitrile (220.5g, 1.0M) in acetone (340g) with 20 stirring at 20-30oC. Stirring was continued for a further 1 hour and the two liquid phases separated. The upper layer ( a solution of the product in acetone) was kept at 20 0 C when 2-methylthio-4- WO 99/02490 PCT/EP98/04948 -6 trifluoromethylbenzonitrile crystallised (213g), m.p.82oC. The yield was 97 %, with product purity >96%. Example 2 5 Methanethiol (278g, 5.78M) was added during 20 minutes to a stirred mixture of acetone (5 litres) and potassium carbonate (593g, 4.29M) at -15 0 C. A solution of 2-nitro-4-trifluoromethylbenzonitrile (618g, 2.86M) in acetone (500ml) was added during 10 minutes. The mixture was allowed to warm to 20oC with stirring for 23 hours and then 10 heated at 55oC for 2 hours to remove most of the methanethiol and then flushed with nitrogen for 4 hours. The mixture was poured onto ice/water, the solid filtered off, washed and dried to give 2-methylthio 4-trifluoromethylbenzonitrile (550g). The yield of product was 89%. 15 Example 3 Sodium thiomethoxide (37g of a 21% aqueous solution, 0.11 M) was added during 2 hours to a solution of 2-chloro 4-trifluoromethylbenzonitrile (20.56g, 0.099M) in acetone (34g) with stirring at 30-35 0 C. After a further 2.5 hours at 30-35 0 C and 3 hours at 20 60'C, a further addition of sodium thiomethoxide (3.4g of a 21% aqueous solution, 0.01 M) was made. The mixture was maintained at 60 oC for 2 hours, cooled and the organic phase evaporated to give 2- WO 99/02490 PCT/EP98/04948 -7 methylthio-4-trifluoromethylbenzonitrile (20.3g), m.p.800C. The yield of product was 91%, with a purity of 97%. Compounds of formulae (II) and (III) and processes for their preparation are known or may be prepared by known methods. Both the 5 compounds of formula (I) above and the herbicidally active compounds which they may be used to prepare are described in the literature, for example in European Patent Publication Nos. 0418175, 0527036,or WO/9500476.

Claims

1. A process for the preparation of a compound of formula (I): CN SRI R4 R2 5 (i) wherein R 1 represents C1- 6 alkyl R 2 represents C 1- 6 haloalkyl, C 1 - 6 alkyl, C 1 - 6 haloalkoxy, C 1 -6 alkoxy, SOnR 5 or halogen; R 4 represents hydrogen, C 1 - 6 haloalkoxy. C 1 - 6 alkoxy. SOnR 5 or 10 halogen; or a 5 or 6-membered heterocyclic ring (which may be unsaturated or partially saturated) containing 1 to 3 hetero atoms selected from oxygen. nitrogen and sulphur, optionally substituted by halogen, C 1- 6 haloalkyl, C 1 - 6 alkyl, C 1 - 6 haloalkoxy. C 1- 6 alkoxy, SOnR5, nitro or cyano; 15 R 5 represents C1- 6 alkyl; and n represents 0, 1 or 2; which comprises reacting a compound of formula (II): WO 99/02490 PCT/EP98/04948 -9 CN 4 R 2 (II) wherein R 2 and R 4 are as hereinbefore defined and R 3 represents nitro or a halogen atom selected from fluorine, chlorine and bromine, 5 with a compound of formula R 1 S-X, wherein R 1 is as hereinbefore defined and X is hydrogen or an alkali metal.

2. A process according to claim 1 in which R 1 represents C 1 -6 alkyl; R 2 represents C 1-6 haloalkyl; and R 4 represents hydrogen.

3. A process according to claim 1 or 2 in which R 1 represents 10 methyl, R2 represents trifluoromethyl and R 4 represents hydrogen.

4. A process according to any one of claims 1 to 3 in which R 3 represents nitro or chlorine.

5. A process according to any one of claims 1 to 4 in which X represents a sodium, potassium or lithium atom. 15

6. A process according to any one of the preceding claims in which the reaction is performed in a solvent selected from aromatic hydrocarbons, ethers, amides, sulphoxides, ketones and mixtures thereof.

7. A process according to claim 6 in which the solvent is 20 acetone, optionally in the presence of water. WO 99/02490 PCTIEP98/04948 - 10

8. A process according to any one of the preceding claims in which the molar ratio of the compound of formula (II): compound of formula R 1 IS-X is from about 1:1 to about 1:4.

9. A process according to claim 8 in which the molar ratio of 5 the compound of formula (II): compound of formula R 1 S-X is from about 1:1 to about 1:2.5.

10. A process according to claim 1 substantially as hereinbefore described in any one of Examples 1 to 3.

11. A compound of formula (I) as defined in claim 1 when 10 prepared by a process according to any one of the preceding claims.